tbuckley/cabot-search huggingface dataset:
EPCO-48. THE SINGLE-CELL AND SPATIAL TRANSCRIPTOMIC ARCHITECTURE OF MENINGEAL SOLITARY FIBROUS TUMORS PHENOCOPIES CEREBRAL VASCULAR DEVELOPMENT AND HOMEOSTASIS
Authors: Kanish Mirchia, Abrar Choudhury, Tara Joseph, Janeth Ochoa Birrueta, Joanna Phillips, Aparna Bhaduri, Elizabeth Crouch, Arie Perry, David Raleigh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with local recurrence and distant metastasis. The cell states and spatial transcriptomic architecture of SFTs are unknown. METHODS Single-cell RNA sequencing or spatial transcriptomic sequencing were performed on 40,022 cells or 23,682 spatial transcriptomes from 12 meningeal SFT samples. Datasets were corrected for batch effects using Harmony and integrated using uniform maniform approximation and projection (UMAP). Clusters were defined using automated cell type classification, cell signature gene sets, cell cycle analysis, and differentially expressed marker genes. Trajectory analyses were performed using RNA velocity and pseudotime. Cell-cell communication analysis was performed using CellChat. RESULTS were validated using immunofluorescence and immunohistochemistry and generalized using comparisons to 30,934 single-cell transcriptomes from 6 meningioma samples, 139,134 perinatal human brain vascular single-cell transcriptomes, 84,138 adult human brain vascular single-cell transcriptomes, and DNA methylation profiles from 8 SFT and 221 meningioma samples. RESULTS Unsupervised hierarchical clustering of DNA methylation profiles revealed molecular distinction of meningeal SFTs from meningiomas. Deconvolution of vascular single-cell types showed SFT cell clusters resembling perinatal or adult fibroblasts, perinatal mitotic endothelia, and adult venous or arterial endothelia. UMAP and trajectory analyses showed SFTs were comprised of 8 interchangeable tumor cell states that were associated with cell adhesion (VCAM1, NCAM2), cell stress (EGR1), cell signaling (NOTCH3), extracellular matrix remodeling (ECM) (ADAMTS6, PLCG2), or protein synthesis pathways (RPL27A, RPL37). Cell-cell communication analyses identified single-cell and spatial interactions between VCAM1- or NCAM2-expressing SFT cells and endothelia or immature neurons in the tumor microenvironment, respectively. Single-cell deconvolution demonstrated evolution of ECM and protein synthesis SFT cells in paired primary/recurrent samples, and evolution of ECM SFT cells and macrophages in paired primary/metastatic samples. CONCLUSIONS The single-cell and spatial transcriptomic architecture of meningeal SFT reveals dynamic cell states that phenocopy cerebral vascular development and homeostasis.
SURG-24. FACTORS PREDICTING REMISSION AND RECURRENCE AFTER SURGICAL TREATMENT OF ACTH SECRETING PITUITARY ADENOMAS - CUSHING’S DISEASE
Authors: Ashish Suri, Rajesh Khadgawat, M C Sharma, Ajay Garg
Journal: Neuro-Oncology (2023)

Abstract Despite recent advances in management, disease persistence and recurrences are common in patients with ACTH secreting pituitary adenomas-Cushing’s disease (CD). The study aims to determine clinical, biochemical, radiological, histological factors that correlate with persistence and recurrence in patients with CD, and also aims to understand the clinico-pathological significance of EGFR-MAPK, NF-kB, SHH pathway activation. Clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD was ambispectively analysed with median follow-up of 8.1years(1-13.29 years). Among the 174 surgeries performed, 140 were primary, 22 were redo, 24 were for paediatric patients and 12 surgeries were performed in Nelson syndrome. In the primary surgery cohort, 74.3% were females and the average age was 28.73years(SD = 10.15). 75% of patients experienced remission after primary surgery compared to 47.4% in redo surgery. The remission rate in paediatric patients was 55.5%. Post-operative day-1 plasma cortisol (p &amp;lt; 0.001;AUC = 0.8894[0.8087-0.9701]) and ACTH (p &amp;lt; 0.001;AUC 0.9[0.7386-1]) levels were seen to be strong independent predictors of remission in primary surgery cohort. Remission rates after endoscopic trans-sphenoidal surgery- TSS were more than those after microscopic TSS, in patients undergoing primary surgery (81.08%vs57.14%;p = 0.008). Presence of adenoma on histopathological examination(HPE) was also strong predictor of disease remission (p = 0.020). On categorising based on surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of non-remission (OR 38.1;95%CI-4.2-348.3) compared to endoscopically operated patients with adenoma on HPE. Lower immune reactivity score (IRS) of NR4A1 was found to correlate with higher remission rates (p = 0.074). However, none of the molecular markers studied - NR4A1, c-Fos, c-Jun, GLI1, pMEK, p44 showed a significant correlation with the preoperative cortisol values. Post-operative day-1 serum cortisol and ACTH are reliable predictors of remission. Additionally, endoscopic approach and histopathological evidence of adenoma are associated with higher remission rate, with both features together raising the odds significantly.
EPCO-38. SINGLE-CELL MULTIMODAL ANALYSIS OF IDH-MUTANT GLIOMAS ASSOCIATES PROGENITOR CELL DEDIFFERENTIATION WITH TUMOR PROGRESSION
Authors: Jingyi Wu, Luis Nicolas Gonzalez Castro, Tyler Miller, Sofia Battaglia, Joshua D'Antonio, Chadi El Farran, Margaret Thompson, Jason Buenrostro, Mario Suva, Bradley Bernstein
Journal: Neuro-Oncology (2023)

Abstract Isocitrate dehydrogenase (IDH) mutant gliomas are progressive, invariably fatal brain tumors affecting young and middle-age adult patients. Previous single-cell transcriptomic characterization of IDH-mutant gliomas has uncovered heterogeneous cell states, with a hierarchy ranging from neural progenitor-like to differentiated cell states. Despite this understanding, the dynamics of these cell states as tumors undergo grade progression, and the factors that facilitate or restrict cell state transitions remain poorly understood. Here, we characterize the cell states of IDH-mutant gliomas spanning all grades using fresh patient samples and compare them with transcriptional programs of normal brain cells. We find that tumor cell states experience a marked shift as tumors undergo progression. In low-grade tumors, predominant cell states mimic slow-cycling oligodendrocyte progenitor cells (OPCs). With grade progression, cell states transition to resemble highly proliferative neural progenitor cells (NPCs). Additionally, single-cell analyses of accessible chromatin (ATAC-seq) revealed novel cellular states defined in chromatin space, which could facilitate this transition. Genetic analyses identified several molecular alterations in high-grade tumors, including loss of DNA methylation, oncogene amplification, and the deletion of genes associated with the interferon (IFN) response. Lastly, we validate the role of DNA hypomethylation in favoring immune evasion with grade progression using an IDH-mutant glioma organoid model. Overall, our findings provide evidence that tumor progression in IDH-mutant gliomas is driven by an interplay of epigenetic and genetic mechanisms that promote more mitotically active cell states as well as decreased anti-tumoral immune activation.
CTIM-14. PHASE 1 SAFETY LEAD-IN AND RANDOMIZED OPEN-LABEL PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH1-MUTANT ASTROCYTOMAS: SAFETY LEAD-IN RESULTS
Authors: Patrick Wen, Katherine Peters, Macarena de la Fuente, Ingo Mellinghoff, Isabel Arrillaga-Romany, Priya Kumthekar, Jennifer Clarke, Vinay Puduvalli, John de Groot, Xiangmin Zhang, Michael Chisamore, Michelle Abshire, Paria Mahboub, Islam Hassan, Jeffrey Knipstein, Timothy Cloughesy
Journal: Neuro-Oncology (2023)

Abstract Isocitrate dehydrogenase 1 mutations (mIDH1) occur in ~80% of grade 2/3 gliomas. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2 enzymes, is an investigational treatment for mIDH gliomas. A neoadjuvant perioperative study in grade 2/3 mIDH gliomas suggested VOR renders the tumor immune microenvironment amenable to immune checkpoint blockade. This study (NCT05484622) evaluates safety/tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) (safety lead-in phase), and CD3+ T-cell infiltration in tumors following preoperative treatment (perioperative phase). Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an IDH1-R132H mutation were dosed in the safety lead-in phase: median age 39 (range, 34–60) years, 3 (43%) female, 6 (86%) grade 3 at screening. Patients received VOR 40 mg orally once daily (QD) plus pembrolizumab 200 mg intravenously once every 3 weeks (Q3W). As of April 29, 2023, patients received a median of 2 (range, 2–5) cycles with six (86%) ongoing; one (14%) discontinued due to disease progression. No dose-limiting toxicities (DLTs), adverse events (AEs) leading to study drug discontinuation, or AEs of special interest (AESI, elevated liver transaminases) were reported during the DLT evaluation period. Six (86%) patients experienced a treatment-related AE, none of which were grade ≥ 3. One (14%) patient experienced a serious, related AE of dysphasia (leading to VOR and pembrolizumab interruption) that subsequently resolved; both drugs were resumed. After the data cut-off, one patient (14%) experienced a grade 2 AESI. Based on safety review committee evaluation, VOR 40 mg QD + pembrolizumab 200 mg Q3W was confirmed as the RCD for the recently initiated perioperative phase. In this phase, ~60 patients will be randomized 1:1:1 to the RCD, VOR 40 mg QD alone, or no treatment prior to surgery. All patients can receive the RCD post-surgery. Funding: Servier and Merck &amp; Co., Inc.
NIMG-13. ROBUSTNESS OF PROGNOSTIC STRATIFICATION IN DE NOVO GLIOBLASTOMA PATIENTS ACROSS 22 GEOGRAPHICALLY DISTINCT INSTITUTIONS: INSIGHTS FROM THE RESPOND CONSORTIUM
Authors: Hamed Akbari, Spyridon Bakas, Jose Garcia, Anahita Fathi Kazerooni, Chiharu Sako, Javier Villanueva-Meyer, Ujjwal Baid, Elizabeth Mamourian, Steven Brem, Robert A Lustig, MacLean P Nasrallah, Donald M O'Rourke, Evan Calabrese, Jeffrey Rudie, Susan Chang, Andreas Rauschecker, Pamela LaMontagne, Daniel S Marcus, Carmen Balana, Jaume Capellades, Josep Puig, Jill Barnholtz-Sloan, Chaitra Badve, Andrew Sloan, Kristin Waite, Rivka Colen, Yoon Seong Choi, Sung Soo Ahn, Adam P Dicker, Adam E Flanders, Wenyin Shi, Brent Griffith, Laila M Poisson, Lisa R Rogers, Thomas C Booth, Rajan Jain, Arnab Chakravarti, Joshua Palmer, Santiago Cepeda, Benedikt Wiestler, Anna Luisa Di Stefano, Kimberley Alexander, Elias R Melhem, Graeme F Woodworth, Peter I Kamel, Pallavi Tiwari, Mariam Aboian, Suyash Mohan, Christos Davatzikos
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Glioblastoma is the most prevalent primary malignant brain tumor in adults, with a median overall survival (OS) of approximately 15 months and only limited advancements in prognostication and survival prediction. This study aims to evaluate an AI-based prognostic stratification model for OS prediction trained on the ReSPOND consortium data and to validate its performance on an independent dataset. METHODS The AI model was trained on a cohort of 2,293 glioblastoma patients from 22 institutions across three continents. For validation, an independent cohort of 78 treatment-naïve patients was used from three institutions. Preoperative structural MRI scans were utilized for feature extraction. Automated segmentation defined three tumor sub-compartments: enhancing, necrotic, and peritumoral T2-FLAIR abnormality. The AI predictor incorporated variables such as patient age, normalized tumor sub-compartment volume, spatial distribution characteristics, and morphologic descriptors. The overall survival predictor index provided a continuous value between 0 and 1 for patient stratification that higher values indicating longer predicted OS. Generalizability was assessed using Leave-One-Cohort-Out-Cross-Validation (LOCOCV) for training data, and the model was subsequently applied to the validation cohort. RESULTS Survival analysis demonstrated a concordance index of 0.64 for LOCOCV training data and 0.59 for the independent validation data, indicating effective prognostic stratification of patients. CONCLUSION Multi-parametric AI assisted image analysis extracts prognostic biomarkers, which correlate with OS in glioblastoma patients. The generalizability of this method was validated using the extensive centralized glioblastoma imaging dataset registry from the ReSPOND consortium and an independent dataset, demonstrating its generalizability across diverse patient populations and acquisition settings. This model holds promise for robust prognostic stratification and prediction in de novo glioblastoma patients.
IMMU-20. MESSENGER RNA CHALLENGE RAPIDLY PREDICTS BRAIN TUMOR RESPONSIVENESS TO CHECKPOINT INHIBITORS
Authors: Paul Castillo, Elizabeth Ogando-Rivas, Hillary Geffrard, Alfonso Pepe, Ruixuan Liu, Duy Nguyen, Diego Pedro, Dingpeng Zhang, Anna DeVries, Sadeem Qdaisat, Adam Grippin, Aida Karachi, Maryam Rahman, Rowan Milner, Jianping Huang, John Ligon, Natalie Silver, Derek Li, Ji-Hyun Lee, Sheila Carrera-Justiz, Frances Weidert, Duane Mitchell, Hector Mendez-Gomez, W Gregory Sawyer, Elias Sayour
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pathogen recognition receptor (PRR) activation is requisite for igniting the immune response and making the tumor microenvironment ‘hot’ during oncogenesis. We theorized that these PRRs would remain present in ICI responsive tumors and could be challenged using pan-PRR mimic to prospectively predict brain cancer immunogenicity and response to immune checkpoint inhibitors (ICIs). METHODS By layering mRNA into multilamellar nanoparticles (ML RNA-NPs), multiple pathogen recognition receptors can be simultaneously activated in individualized cancer cells serving as a broad screen to test tumor immunogenicity. We challenged murine brain tumor lines known to respond (GL261 and SMA-560) or resist ICI treatment (KR158b and CT2A) with ML RNA-NPs and analyzed downstream production of proinflammatory cytokines as predictors of ICI response. RESULTS We demonstrated that ML-RNA-NPs can activate multiple PRRs simultaneously. Following ML RNA-NP challenge, ICI responsive tumors GL261 and SMA-560 (compared to more ICI resistant lines KR158b and CT2A) elicited increased production in pro-inflammatory cytokines such as IFN-β and IL-6 and in CCL4. To further develop this work into a commercially viable tool to predict ICI response, we developed 3D modeling of glial tumors for ML RNA-NP challenge and immunogenicity prediction. We enrolled canines with primary gliomas and began growing their tumoroids in 3D using liquid-like solid (LLS) technology. Using this pipeline, we successfully perfused 3D tumoroids with ML RNA-NP demonstrating ability to set up real-time patient derived explants to predict immunogenicity. We demonstrated that mRNA perfusion of 3D tumoroids elicited similar cytokine response observed with 2D culture of cell-lines. CONCLUSION Our results indicate that cytokine signatures following ML RNA-NP challenge differ significantly from ICI responsive versus non-responsive brain tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICIs.
ANGI-06. BIOLOGY OF GLIOBLASTOMA INVASION: A SINGLE-CELL LEVEL ANALYSIS OF TUMOR CORE VS. INFILTRATING EDGE
Authors: Balagopal Pai, Wan Sze Chang, Elena Zaslavsky, Nadejda Tsankova
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly proliferative and diffusely infiltrating tumor, consisting of a necrotic core showing extensive microvascular proliferation and an infiltrating edge that extends beyond the surgical resection margin. The aggressiveness of GBM can be attributed to the existence of glioma stem-like cell populations (GSC) at this infiltrating edge. Although many studies have characterized GSC biology in culture, their contributions to invasion in vivo, and in the context of their microenvironment, remains poorly understood. In this study, we used macro-dissected biopsies of the tumor core and the infiltrative edge from six genetically-distinct glioblastoma tumors, to generate a spatiotemporal map of tumor invasion at a single-cell level. Unbiased clustering of ~40,000 nuclei and integrated analysis identified various cell types composing the tumor microenvironment, with predominance of tumor cells at the core and non-neoplastic cells at the edge, as expected. Inferred copy number alterations based on gene expression confirmed tumor cell identity in the core and the edge datasets. Differential expression analysis of core vs. edge tumor clusters revealed distinct transcriptomic signatures including several genes previously implicated in GBM invasion, such as EGFR, matrix metalloproteinases, and MAPK signaling pathway members. Several genes from this newly defined “GBM invasion signature” were further validated in a PDX invasion model, in which the transcriptome within the tumor core and infiltrative edge were similarly sequenced and analyzed at the single cell level. We are currently employing 10X-visium combined with immunohistochemistry to spatially deconvolute and corroborate the defined GBM invasion/infiltration signature at the tissue level in tumor biopsies. Overall, our study aims to provide high resolution map of glioma tumor invasion that can prioritize new and unique targetable pathways.
DNAR-13. TARGETING THE DNA DAMAGE RESPONSE IN GLIOBLASTOMA PROPAGATING CELLS: FROM MOLECULAR MECHANISMS TO PRECISION MEDICINE
Authors: Alexandros Pailas, Katrin Neumann, Céline Jeanty, Christel Herold-Mende, Reka Toth, Petr Nazarov, Joshua Scalisi, Virginie Neirinckx, Bernard Rogister, Eric Van Dyck
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive and lethal primary tumor of the central nervous system (CNS). Despite surgical resection and a combination of radiotherapy and alkylation chemotherapy, the median survival for patients with newly diagnosed GBM is only ~ 14 months. Among the many challenges confronting clinicians are subpopulations of tumor-propagating cells named GBM Stem-like Cells (GSCs), which have been proposed to drive treatment resistance and foster tumor relapse. At the mechanistic level, GSCs have been shown to display constitutive activation of the DNA damage response (DDR) due to chronic replication stress (RS), which enhances their ability to repair the DNA lesions induced by chemoradiation. Thus, developing new therapeutic strategies against glioblastoma is of paramount importance. Cell cycle regulation and DNA damage response are two crucial molecular networks altered in most cancer types. In this context, we have previously identified a DNA repair and cell cycle gene expression signature that results in the classification of GBM tumors in two major groups, G1 and G3, which differ in the expression of survival and proliferation pathways. Using bioinformatics analysis of the GLASS consortium database, we have created an exhaustive oncopanel of the molecular alterations defining the G1 and G3 groups. Furthermore, using G1- and G3-patient-derived GSC cell lines as experimental models, we have identified crucial differences in the mechanisms orchestrating the cell cycle, DDR, and treatment resistance between G1 and G3 cells. Finally, we have also identified group-specific therapeutic strategies combining repositioned FDA-approved drugs with the inhibition of crucial DDR factors. Our long-term goals are i) to understand the molecular basis behind the differential response to DNA damage and replication stress developed by G1 and G3 cells and ii) to propose group-specific, DDR-based combination therapies that prevent treatment resistance and promote long-lasting treatment.
QOL-05. EXPLORATORY ANALYSIS OF COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA (CBT-I) AMONG PATIENTS WITH PRIMARY BRAIN TUMOR: EFFECTS ON DEPRESSION, ANXIETY, AND LIFE QUALITY
Authors: Autumn Lanoye, Amber Fox, Kelcie Willis, Alicia M Zukas, Ashlee Loughan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Sleep disturbance is among the most common complaints endorsed by patients with a brain tumor diagnosis, yet the delivery of behavioral insomnia treatment is not standard practice in neuro-oncology. Our pilot trial of a 6-session group-based telehealth CBT-I program among primary brain tumor patients demonstrated clinically significant improvements in self-reported insomnia, fatigue, and sleep quality. In other cancer patient samples, CBT-I is also associated with improvements in psychosocial outcomes beyond sleep; thus, the aim of this exploratory analysis was to examine change in depression, anxiety, and life quality among primary brain tumor patients enrolled in CBT-I. METHODS This was a single-arm ORBIT Model Phase IIa proof-of-concept trial. N = 40 cognitively-intact participants (Mage = 52.4 + 12 years; 50.0% female) with a primary brain tumor and insomnia enrolled in a 6-week group-based telehealth CBT-I intervention with weekly 90-minute sessions led by graduate students in clinical psychology. Questionnaires (PHQ-9, GAD-7, EORTC-QLQ-30) were completed at baseline and 6 weeks. Within-person clinically significant improvement was calculated for intervention completers (n = 34) based on established cutoffs. RESULTS Approximately one-third of participants experienced clinically significant improvements in symptoms of depression (n = 12, 35.3%) and generalized anxiety (n = 11, 32.3%) following CBT-I, with 0 participants experiencing a clinically significant worsening of symptoms. Thirty-two of thirty-four participants (94.1%) reported clinically significant improvement in at least 1 domain of life quality spanning physical, role, emotional, and/or social functioning. CONCLUSIONS Findings suggest that a brief behavioral intervention for insomnia, CBT-I, may improve depression, anxiety, and life quality in addition to sleep among primary brain tumor patients. RESULTS from this proof-of-concept trial suggest proceeding to a test of CBT-I in comparison to a control group in order to bolster internal validity. In addition, future studies will examine sleep and related psychosocial outcomes over a longer follow-up period to assess maintenance of intervention effects.